The present invention relates to novel thyroid receptor ligands and, more particularly, relates to novel 6-azauracils, and derivatives thereof, which are useful in the treatment of obesity, overweight condition, hyperlipidemia, thyroid disease, hypothyroidism, thyroid cancer and related disorders and diseases such as diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, hypercholesteremia, depression, osteoporosis, cardiac arrhythmias, glaucoma and congestive heart failure. Also provided are methods, pharmaceutical compositions and kits for treating such diseases and disorders.
It is generally accepted that thyroid hormones, specifically, biologically active iodothyronines, are critical to normal development and to maintaining metabolic homeostasis. Thyroid hormones stimulate the metabolism of cholesterol to bile acids and enhance the lipolytic responses of fat cells to other hormones.
Thyroid hormones also affect cardiac function both directly and indirectly, e.g., by increasing the metabolic rate. For example, tachycardia, increased stroke volume, increased cardiac index, cardiac hypertrophy, decreased peripheral vascular resistance and increased pulse pressure are observed in patients with hyperthyroidism.
Disorders of the thyroid are generally treated with hormone replacement by administering either naturally occurring thyroid hormones or thyromimetic analogues which mimic the effects of thyroid hormones.
Two naturally occurring thyroid hormones, namely, thyroxine or 3,5,3xe2x80x2,5xe2x80x2-tetraiodo-L-thyronine (commonly referred to as xe2x80x9cT4xe2x80x9d) and 3,5,3xe2x80x2-triiodo-L-thyronine (commonly referred to as xe2x80x9cT3xe2x80x9d), are shown below: 
T3 is the more biologically active of the two and, as will be appreciated from the structural formulae provided above, differs from T4 by the absence of the 5xe2x80x2 iodine. T3 may be produced directly from the thyroid gland, or, in peripheral tissues, by the removal of the 5xe2x80x2 iodine by deiodinase enzymes. Thyromimetic analogs are often designed to be structurally similar to T3. In addition, naturally occurring metabolites of T3 are known.
As discussed above, thyroid hormones affect cardiac functioning, for example, by causing an increase in the heart rate and, accordingly, an increase in oxygen consumption. While the increase in oxygen consumption may result in certain desired metabolic effects, nonetheless, it does place an extra burden on the heart, which in some situations, may give rise to damaging side effects. Therefore, as is known in the art, such as described by A. H. Underwood et al. in an article published in Nature, Vol. 324: pp. 425-429 (1986), efforts have been made to synthesize thyroid hormone analogs which function to lower lipids and serum cholesterol without generating the adverse cardiac effects referred to above.
Certain 6-azauracils and derivatives thereof are known in the art. U.S. Pat. Nos. 3,905,971 and 3,912,723 disclose certain 2-phenyl-as-triazine-3,5(2H,4H)diones and certain 2-substituted-phenyl-as-triazine-3,5(2H,4H)diones and their use as agents for the control of coccidiosis.
U.S. Pat. Nos. 3,883,527 and 3,883,528 disclose processes for producing certain 2-aryl-as-triazine-3,5(2H,4H)-diones, which are useful as coccidiostats.
Canadian Patent Nos. 979457 and 992538 disclose certain 2-phenyl-as-triazine-3,5(2H, 4H)diones, derivatives thereof, compositions containing said compounds and process for preparing said compounds, which compounds are useful in controlling coccidiosis.
U.S. Pat. Nos. 3,896,172 and 3,852,289 disclose processes for preparing certain 1,2,4-triazine-3,5(2H,4H)diones having a p-chlorophenylthio-substituted 2-aryl moiety, which compounds are useful as coccidiostats.
U.S. Pat. Nos. 3,882,115 and 3,883,525 disclose processes for preparing certain 1,2,4-triazine-3,5(2H,4H)diones having a 2-aryl moiety which is substituted with, for example, 2-chlorophenoxy and 2-chloro-4-(N-methyl-N-ethylsulfamoyl)phenoxy.
U.S. Pat. No. 5,256,631 and South African Patent No. 91/7390 disclose certain substituted 1,2,4-triazinediones, processes for preparing them and their use as antiprotozoal agents. German Patent No. 25 32 363 discloses certain 1,2,4-triazin-3,5(2H,4H)-dione compounds having a 4-amino-phenoxy-substituted 2-phenyl group. South African Patent No. 73/9126 discloses a process for preparing certain 2-aryl-6-carboxy-1,2,4-triazine-3,5(2H,4H)-diones.
U.S. Pat. No. 4,640,917 discloses substituted 2-phenyl-hexahydro-1,2,4-triazine-3,5-diones which are useful for controlling protozoal diseases. U.S. Pat. No. 4,198,407 discloses certain substituted 2-phenyl-1,2,4-triazine-3,5(2H,4H)-diones and coccidiostatic agents containing them.
Published European Patent Application 0 737 672 discloses a method of producing 1,2,4-triazin-3-one derivatives having a substituent at the 2-position.
U.S. Pat. No. 4,239,888 discloses certain 1-phenyluracils and their utility as coccidiostats.
B. L. Mylari et al., J.Med.Chem. 1977, 20, 475-483; M. W. Miller et al., J.Med.Chem. 1979, 22, 1483-1487; and M. W. Miller et al., J.Med.Chem. 1980, 23, 1083-1087; discloses certain anticoccidial derivatives of 6-azauracil.
M. W. Miller et al., J.Med.Chem. 1981, 24,1337-1342, discloses certain anticoccidial derivatives of 6-azauracil having phenyl sulfide and phenyl sulfone side chains.
R. D. Carroll et al., J.Med.Chem. 1983, 26, 96-100, discloses certain anticoccidial derivatives of 6-azauracil having a p-benzophenone side chain.
K.-B. Rhyu et al., J. Chem. Inf. Comput. Sci. (1996), 36(3), 620; K.-B. Rhyu et al., J. Chem. Inf. Comput. Sci. (1995), 35(4), 771-8; A. C. Good et al., J. Med. Chem. (1993). 36(20), 2929-37; J. W. McFarland, J. Med. Chem. (1992), 35 (14), 2543-50; and J. W. McFarland et al., J. Med. Chem. (1991). 34 (6), 1908-11; disclose various techniques for studying the quantitative structure-activity relationships among certain anticoccidial 2-(substituted phenyl)-1,2,4-triazine-3,5 (2H,4H)-diones.
A. N. Chekhlov et al., Dokl. Akad. Nauk (1993), 329 (5), 603-7, discloses the molecular and crystal structure of 2-[3,5-dichloro-4-(m-trifluoromethylphenylthio)phenyl]-1,2,4-triazine-3,5(2H,4H)-dione.
N. S. Zefirov et al., Dokl. Akad. Nauk (1992), 327 (4-6), 504-8, discloses the quantitative relationship between the structure of 2-substituted 1,2,4-triazine-3,5(2H,4H)-diones and their anticoccidial activity.
A. P. Ricketts et al., Antimicrob. Agents Chemother. (1992), 36 (10), 2338-41, discloses the study of the relationship between the in vitro anticoccidial activity and the in vivo efficacy of compounds such as the aryl triazine compound, 3-chloro-4-[2-chloro-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-6-methylphenoxy]-N-ethyl-N-methyl-benzenesulfonamide.
M. J. Lynch and S. K. Figdor, J. Agric. Food Chem. (1977), 25 (6),1344-53, disclose tissue residue and comparative metabolism studies on tiazuril, 2-[3,5-dimethyl-4-(4-chlorophenylthio)phenyl-as-triazine-3,5 (2H, 4H)dione, in the chicken, rat, dog and monkey.
J. F. Ryley et al., Parasitology (1974), 68 (Pt. 1), 69-79, discloses the anticoccidial activity of an azauracil derivative, 2-[3,5-dichloro-4-(4-chlorophenylthio)phenyl-as-triazine-3,5 (2H, 4H)dione.
All of the documents cited herein, including the foregoing, are incorporated by reference herein in their entireties.

isomers thereof, prodrugs of said compounds or isomers, or pharmaceutically acceptable salts of said compounds, isomers or prodrugs; wherein W is (a) xe2x80x94Oxe2x80x94, (b) xe2x80x94S(O)mxe2x80x94, (c) xe2x80x94NR30xe2x80x94, (d) xe2x80x94C(O)xe2x80x94, (e) xe2x80x94HCxe2x95x90CHxe2x80x94, (f) xe2x80x94CH2xe2x80x94, (g)- CHFxe2x80x94, (h) xe2x80x94CF2xe2x80x94 or (i) xe2x80x94CH(OH)xe2x80x94;
R1 and R2 are independently (a) hydrogen, (b) halogen, (c) xe2x80x94(C1-C6)alkyl, (d) xe2x80x94CN, (e) xe2x80x94OR12 or (f) -trifluoromethyl;
R3 is (a) hydrogen, (b) halogen, (c) xe2x80x94(C1-C6)alkyl optionally substituted with one to three substituents independently selected from the group consisting of halogen, xe2x80x94OCF3 and xe2x80x94CF3, (d) xe2x80x94CN, (e) xe2x80x94OR12, (f) -trifluoromethyl, (g) xe2x80x94NO2, (h) xe2x80x94SO2xe2x80x94R13, (i) xe2x80x94C(O)2R9, (j) xe2x80x94C(O)NR19R20, (k) xe2x80x94C(O)R16, (I) xe2x80x94NR21C(O)xe2x80x94NR21R22, (m) xe2x80x94NR19xe2x80x94C(O)R20 or (n) xe2x80x94NR17R18;
R4 is (a) xe2x80x94C(R14)(R15)(R16), (b) xe2x80x94(C0-C3)alkyl-NR17R18, (c) xe2x80x94C(O)NR19R20, (d) xe2x80x94NR19xe2x80x94C(O)xe2x80x94R20, (e) xe2x80x94(C0-C3)alkyl-NR21xe2x80x94C(O)xe2x80x94NR21R22, (f) xe2x80x94S(O)mxe2x80x94R22, (g) xe2x80x94S(O)2xe2x80x94NR21R22, (h) xe2x80x94NR21xe2x80x94S(O)2xe2x80x94R22, (i) -aryl, (j) -het, (k) xe2x80x94OR33 or (I) halogen; provided that in substituents (f) and (h), R22 is other than xe2x80x94OR34; and provided that when substituent (b) is xe2x80x94(C0)alkyl-NR17R18, R18 is other than xe2x80x94C(O)xe2x80x94R28 or xe2x80x94S(O)2xe2x80x94R29;
or R3 and R4 may be taken together to form a carbocyclic ring of Formula xe2x80x94(CH2)bxe2x80x94 or a heterocyclic ring selected from the group consisting of xe2x80x94Qxe2x80x94(CH2)cxe2x80x94 and xe2x80x94(CH2)jxe2x80x94Qxe2x80x94(CH2)kxe2x80x94 wherein Q is O, S or NR25; wherein said carbocyclic ring is optionally substituted with one or more substituents independently selected from Group V; and wherein said heterocyclic ring is optionally substituted with one or more substituents independently selected from Group Z;
R5 is xe2x80x94OR23;
or R4 and R5 may be taken together to form a heterocyclic ring selected from the group consisting of xe2x80x94CR31xe2x95x90CR32xe2x80x94NHxe2x80x94, xe2x80x94Nxe2x95x90CR31xe2x80x94NHxe2x80x94, xe2x80x94CR31xe2x95x90CR32xe2x80x94Oxe2x80x94 and xe2x80x94CR31xe2x95x90CR32xe2x80x94Sxe2x80x94;
R6 is (a) hydrogen, (b) halogen, (c) xe2x80x94(C1-C6)alkyl optionally substituted with one to three substituents independently selected from the group consisting of halogen, xe2x80x94OCF3 and xe2x80x94CF3, (d) xe2x80x94CN, (e) xe2x80x94OR12, (f) -trifluoromethyl, (g) xe2x80x94NO2, (h) xe2x80x94SO2xe2x80x94R13, (i) xe2x80x94C(O)2R9, (j) xe2x80x94C(O)NR19R20, (k) xe2x80x94C(O)R16, (I) xe2x80x94NR21C(O)NR21R22, (m) xe2x80x94NR19xe2x80x94C(O)R20 or (n) xe2x80x94NR17R18;
R7 is (a) hydrogen, (b) xe2x80x94(C1-C4)alkyl wherein each carbon atom is optionally substituted with 1 to 3 halo atoms or (c) xe2x80x94(CH2)nCOOR9;
R8 is (a) hydrogen, (b) xe2x80x94(C1-C6)alkyl, (c) xe2x80x94C(O)xe2x80x94OR9, (d) xe2x80x94C(O)NR10R11 or (e) xe2x80x94CN; provided that in substituent (c), R9 is other than methyl or ethyl; and provided that in substitutent (d), R10 and R11 are not both hydrogen;
R9 is (a) xe2x80x94(C1-C12)alkyl optionally substituted with one or more substitutents independently selected from Group V, (b) xe2x80x94(C2-C12)alkenyl optionally substituted with phenyl, (c) xe2x80x94(C2-C12)dialkenyl, (d) xe2x80x94(C3-C10)cycloalkyl, (e) -aryl or (f) -het;
R10 and R11 are independently (a) hydrogen, (b) xe2x80x94(C1-C12)alkyl optionally substituted with one or more substituents independently selected from Group V, (c) xe2x80x94(C3-C10)cycloalkyl optionally substituted with one or more substituents independently selected from Group V, (d) xe2x80x94(C2-C12)alkenyl or (e) -het;
or R10 and R11 for any occurrence may be taken together with the nitrogen atom to which are they attached to form het;
R12 is (a) hydrogen or (b) xe2x80x94(C1-C6)alkyl wherein each carbon atom is optionally substituted with 1 to 3 fluoro atoms;
R13 is (a) xe2x80x94(C1-C12)alkyl optionally substituted with one or more substituents independently selected from Group V, (b) xe2x80x94(C2-C12)alkenyl, (c) xe2x80x94(C3-C10)cycloalkyl, (d) xe2x80x94NR17R18, (e) -aryl or (f) -het;
R14 is (a) hydrogen, (b) xe2x80x94(C1-C6)alkyl or (c)xe2x80x94Oxe2x80x94R34;
R15 is (a) hydrogen or (b) xe2x80x94(C1-C6)alkyl;
or R14 and R15 are taken together with the carbon atom to which they are attached to form a carbonyl group;
R16 is (a) hydrogen, (b) xe2x80x94(C1-C6)alkyl wherein each carbon atom is optionally substituted with 1 to 3 fluoro atoms, (c) xe2x80x94(C0-C6)alkyl-(C3-C10)cycloalkyl, (d) xe2x80x94(C0-C6)alkyl-aryl or (e) xe2x80x94(C0-C6)alkyl-het;
R17 is (a) hydrogen, (b) xe2x80x94(C1-C12)alkyl optionally substituted with one or more substituents independently selected from Group V, (c) -aryl, (d) -het, (e) xe2x80x94OR34 or (f) xe2x80x94(C3-C10)cycloalkyl;
R18 is (a) hydrogen, (b) xe2x80x94(C1-C12)alkyl optionally substituted with one or more substituents independently selected from Group V, (c) -aryl, (d) -het, (e) xe2x80x94C(O)xe2x80x94R28, (f) xe2x80x94S(O)2xe2x80x94R29, (g) xe2x80x94OR34 or (h) xe2x80x94(C3-C10)cycloalkyl;
or R17 and R18 for any occurrence are taken together with the nitrogen atom to which they are attached to form het;
R19 and R20 for each occurrence are independently (a) hydrogen, (b) xe2x80x94(C1-C12)alkyl optionally substituted with one or more substituents independently selected from Group V, (C) xe2x80x94(C0-C6)alkyl-aryl, (d) xe2x80x94(C0-C6)alkyl-het, (e) xe2x80x94C(O)xe2x80x94NR26R27, (f) xe2x80x94C(O)xe2x80x94R28, (g) xe2x80x94S(O)2xe2x80x94R29, (h) xe2x80x94OR34 or (i) xe2x80x94(C3-C10)cycloalkyl;
or R19 and R20 for any occurrence are taken together with the nitrogen atom to which they are attached to form het;
R21 and R22 for each occurrence are independently (a) hydrogen, (b) xe2x80x94(C1-C12)alkyl optionally substituted with one to three substituents independently selected from Group V, (c)-aryl, (d) -het, (e) xe2x80x94(C3-C10)cycloalkyl or (f) xe2x80x94OR34;
or R21 and R22 are taken together with the nitrogen atom to which they are attached to form het;
R23 is (a) hydrogen, (b) xe2x80x94(C1-C4)alkyl optionally substituted with one or more substituents independently selected from Group V or (c) xe2x80x94C(O)xe2x80x94R24;
R24 is (a) hydrogen, (b) xe2x80x94(C1-C12)alkyl optionally substituted with one or more substituents independently selected from Group V, (c) xe2x80x94(C2-C12)alkenyl, (d) xe2x80x94(C3-C10)cycloalkyl, (e) -aryl or (f) -het;
R25 for each occurrence is independently (a) hydrogen, (b) xe2x80x94(C1-C6)alkyl, (c) xe2x80x94COR29 or (d) xe2x80x94SO2R29;
R26 and R27 for each occurrence are independently (a) hydrogen, (b) xe2x80x94(C1-C6)alkyl, (c) xe2x80x94(C3-C10)cycloalkyl, (d) xe2x80x94(C0-C6)alkyl-aryl, or (e) xe2x80x94(C0-C6)alkyl-het,
R28 is (a) hydrogen, (b) xe2x80x94(C1-C12)alkyl optionally substituted with one or more substituents independently selected from Group V, (c) xe2x80x94(C2-C12)alkenyl, (d) xe2x80x94(C3-C10)cycloalkyl, (e) -aryl or (f) -het;
R29 is (a) xe2x80x94(C1-C12)alkyl optionally substituted with one or more substituents independently selected from Group V, (b) xe2x80x94(C2-C12)alkenyl, (c) xe2x80x94(C3-C10)cycloalkyl, (d) -aryl or (e) -het;
R30 is (a) hydrogen, (b) xe2x80x94(C1-C12)alkyl optionally substituted with one or more substituents independently selected from Group V, (c) xe2x80x94(C1-C12)alkenyl, (d) xe2x80x94(C3-C10)cycloalkyl, (e) xe2x80x94C(O)xe2x80x94R31 or (f) xe2x80x94S(O)mxe2x80x94R32;
R31 is (a) hydrogen, (b) xe2x80x94(C1-C12)alkyl optionally substituted with one or more substituents independently selected from Group V, (c) xe2x80x94(C2-C12)alkenyl, (d) xe2x80x94(C3-C10)cycloalkyl, (e) -aryl, (f) -het or (g) xe2x80x94OR34;
R32 is (a) hydrogen, (b) xe2x80x94(C1-C12)alkyl optionally substituted with one or more substituents independently selected from Group V, (c) xe2x80x94(C2-C12)alkenyl, (d) xe2x80x94(C3-C10)cycloalkyl, (e) -aryl or (f) -het;
R33 is (a) xe2x80x94(C0-C6)alkyl-aryl, (b) xe2x80x94(C0-C6)alkyl-het, (c) xe2x80x94(C7-C12)alkyl optionally substituted with one or more substituents independently selected from Group V, (d) xe2x80x94(C1-C6)alkyl wherein at least one carbon atom is substituted with 1 to 3 fluoro atoms, (e) xe2x80x94(C2-C12)alkenyl or (f) xe2x80x94(C3-C10)cycloalkyl;
R34 is (a) -aryl, (b) -het, (c) xe2x80x94(C1-C12)alkyl optionally substituted with one or more substituents independently selected from Group V, (d) xe2x80x94(C2-C12)alkenyl or (e) xe2x80x94(C3-C10)cycloalkyl;
xe2x80x94(C3-C10)cycloalkyl for each occurrence is a fully or partially saturated mono-, bi- or tricyclic ring containing three to ten carbon atoms; wherein in the bicyclic ring, a monocyclic cycloalkyl ring is spiro fused to another cycloalkyl ring or is fused via two carbon atoms to a benzene ring or another cycloalkyl ring; and wherein in the tricyclic ring, a bicyclic ring is spiro fused to a cycloalkyl ring or is fused via two atoms to a benzene ring or another cycloalkyl ring;
said xe2x80x94(C3-C10)cycloalkyl optionally contains one to three bridging atoms independently selected from carbon, oxygen, sulfur and nitrogen; said bridging atoms are attached to two carbon atoms in the ring; and said bridging atoms are optionally substituted with one to three groups independently selected from xe2x80x94(C1-C6)alkyl and hydroxy;
said cycloalkyl ring is optionally substituted on one ring if the moiety is monocyclic, on one or both rings if the moiety is bicyclic, or on one, two or three rings if the moiety is tricyclic, with one or more substitutents independently selected from Group V;
Group V is (a) xe2x80x94(C1-C6)alkyl optionally substituted with one or two hydroxy, (b) xe2x80x94(C2-C5)alkynyl, (c) -halogen, (d) xe2x80x94NR35R36, (e) xe2x80x94NO2, (f) xe2x80x94OCF3, (g) xe2x80x94OR37, (h) xe2x80x94SR37, (i) -oxo, (j) -trifluoromethyl, (k) xe2x80x94CN, (I) xe2x80x94C(O)NR35xe2x80x94OH, (m) xe2x80x94COOR35, (n) xe2x80x94Oxe2x80x94C(O)xe2x80x94(C1-C6)alkyl, (o) xe2x80x94(C3-C10)cycloalkyl optionally substituted with CN, (p) xe2x80x94(C0-C6)alkyl-aryl, (q) xe2x80x94(C0-C6)alkyl-het, (r) xe2x80x94C(O)xe2x80x94(C1-C6)alkyl or (s) xe2x80x94C(O)-aryl;
R35 and R36 for each occurrence are independently (a) hydrogen, (b) xe2x80x94(C1-C6)alkyl or (c) xe2x80x94(C0-C6)alkyl-aryl;
R37 is (a) hydrogen, (b) xe2x80x94(C1-C6)alkyl optionally substituted with one or more halo, hydroxy or methoxy, (c) xe2x80x94(C0-C6)alkyl-aryl or (d) xe2x80x94(C0-C6)alkyl-het;
aryl is (a) phenyl optionally substituted with one or more substituents independently selected from Group Z; (b) naphthyl optionally substituted with one or more substituents independently selected from Group Z or (c) biphenyl optionally substituted with one or more substituents independently selected from Group Z;
het for each occurrence is a 4-, 5-, 6-, 7- and 8-membered fully saturated, partially saturated or fully unsaturated mono-, bi- or tricyclic heterocyclic ring containing from one to four heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen; wherein in the bicyclic ring, a monocyclic heterocyclic ring is spiro fused to a xe2x80x94(C3-C8)cycloalkyl ring or to another heterocyclic ring which is fully or partially saturated; or is fused via two atoms to a benzene ring, a xe2x80x94(C3-C8)cycloalkyl ring or another heterocyclic ring; and wherein in the tricyclic ring, a bicyclic ring is spiro fused to a xe2x80x94(C3-C8)cycloalkyl ring or to another heterocyclic ring which is fully or partially saturated; or is fused via two atoms to a benzene ring, a (C3-C6)cycloalkyl ring, or another heterocyclic ring;
said het optionally contains one to three bridging atoms independently selected from oxygen, sulfur and nitrogen; said bridging atoms are attached to two other atoms in the ring; and said bridging atoms are optionally substituted with one to three groups independently selected from xe2x80x94(C1-C6)alkyl and hydroxy;
said het optionally has one or two oxo groups substituted on carbon or one or two oxo groups substituted on sulfur;
said het is optionally substituted on carbon or nitrogen, on one ring if the moiety is monocyclic, on one or both rings if the moiety is bicyclic, or on one, two or three rings if the moiety is tricyclic, with one or more substituents independently selected from Group Z;
Group Z for each occurrence is independently (a) hydrogen, (b) halogen, (c) trifluoromethyl, (d) hydroxy, (e) xe2x80x94OCF3, (f) xe2x80x94CN, (g) xe2x80x94NO2, (h) xe2x80x94(C1-C6)alkyl optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, xe2x80x94OCF3 and xe2x80x94CF3, (i) xe2x80x94(C2-C6)alkenyl optionally substituted with phenyl, (j) xe2x80x94(C2xe2x80x94C5)alkynyl, (k) xe2x80x94(C1-C6)alkoxy, (I) xe2x80x94(C0-C6)alkyl-phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OCF3, xe2x80x94CF3, xe2x80x94(C1-C4)alkyl, xe2x80x94(C1-C4)alkoxy and xe2x80x94C(O)CH3, (m) xe2x80x94(C0-C6)alkyl-naphthyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OCF3, xe2x80x94CF3, xe2x80x94(C1-C4)alkyl, xe2x80x94(C1-C4)alkoxy and xe2x80x94C(O)CH3, (n) xe2x80x94C(O)2R35, (o) xe2x80x94(C0-C6)alkyl-C(O)NR35R36, (p) xe2x80x94(C0-C6)alkyl-C(O)R36, (q) xe2x80x94NR35R36, (r) xe2x80x94NR35xe2x80x94C(O)NR35R36, (s) xe2x80x94NR35xe2x80x94C(O)R36, (t) xe2x80x94OR37, (u) xe2x80x94SR37, (v) xe2x80x94(C3-C10)cycloalkyl, (w) xe2x80x94(C0-C6)alkyl-pyridinyl optionally substituted with one or more xe2x80x94(C1-C6)alkyl which is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy and halo, (x) xe2x80x94(C0-C6)alkyl-piperidinyl optionally substituted with one or more xe2x80x94(C1-C6)alkyl which is optionally substituted with one or more substituents independently selected from hydroxy and halo, (y) xe2x80x94SO2xe2x80x94R37, (z) xe2x80x94SO2xe2x80x94NR37R36 or (a1) xe2x80x94S-phenyl-CH2OH;
R38 is (a) xe2x80x94(C1-C6)alkyl, (b) xe2x80x94(C0-C6)alkyl-phenyl, (c) xe2x80x94(C0-C6)alkyl-phenanthrenyl optionally substituted with one to three CF3, (d) xe2x80x94(C0-C6)alkyl-pyrrolidinyl or (e) xe2x80x94(C0-C6)alkyl-morpholinyl;
or any two Z Groups for any occurrence in the same variable may be taken together to form (a) a carbocyclic ring of the formula xe2x80x94(CH2)exe2x80x94 or (b) a heterocyclic ring selected from the group consisting of xe2x80x94O(CH2)fOxe2x80x94, xe2x80x94(CH2)gNHxe2x80x94 and xe2x80x94CHxe2x95x90CHNHxe2x80x94;
m is 0, 1 or 2;
n is 0, 1, 2 or 3;
b is 3, 4, 5, 6 or 7;
c, f, g, j and k are each independently 2, 3, 4, 5 or 6; and
e is 3, 4, 5, 6 or 7;
provided that in a compound of Formula I: 1) the substituent xe2x80x94C(R14)(R15)(R16) in R4 is other than (C1-C4)alkyl; and 2) R4 is halo only when R8 is xe2x80x94C(O)xe2x80x94OR9 or xe2x80x94C(O)NR10R11.
More particularly, the present invention provides compounds of Formula I, and prodrugs, isomers or pharmaceutically acceptable salts thereof, wherein W is oxygen.
More particularly, the present invention provides compounds of Formula I, and prodrugs, isomers or pharmaceutically acceptable salts thereof, wherein R1 is located at the 3 position, R2 is located at the 5 position, R3 is located at the 2xe2x80x2 position, R4 is located at the 3xe2x80x2 position, R5 is located at the 4xe2x80x2 position and R6 is located at the 5xe2x80x2 position.
More particularly, the present invention provides compounds of Formula I, and prodrugs, isomers or pharmaceutically acceptable salts thereof, wherein R3 is hydrogen, R5 is hydroxy or methoxy, R6 is hydrogen, R7 is hydrogen and R8 is hydrogen.
More particularly, the present invention provides compounds of Formula I, and prodrugs, isomers or pharmaceutically acceptable salts thereof, wherein R1 and R2 are each independently methyl, bromo or chloro.
More particularly, the present invention provides compounds of Formula I, and pharmaceutically acceptable salts thereof, wherein R4 is S(O)2NR21R22; R21 is hydrogen or methyl; and R22 is (a) xe2x80x94(C5-C8)alkyl, (b) bicyclo[2.2.1]hept-2-yl, (c) 1,2,3,4-tetrahydro-naphthalen-1-yl, (d) cyclobutyl, (e) cyclopentyl, (f) cyclohexyl or (g) phenyl optionally substituted with one or more fluoro. Even more particularly, the present invention provides such compounds, and pharmaceutically acceptable salts thereof, wherein R1 is methyl or chloro, R2 is methyl or chloro, R5 is hydroxy and R21 is hydrogen.
In addition, more particularly, the present invention provides compounds of Formula I, and pharmaceutically acceptable salts thereof, wherein R4 is S(O)2NR21R22; R21 and R22 are taken together with the nitrogen atom to which they are attached to form het; and het is (a) piperidinyl optionally substituted with one or more substituents independently selected from the group consisting of methyl and phenyl, (b) pyrrolidinyl, (c)1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octanyl, (d) indolinyl, (e) spiro[8-azabicyclo[3.2.1 ]octane-3,2xe2x80x2-(3xe2x80x2H)-dihydro-furan], (f) spiro[8-azabicyclo[3.2.1]octane-3,2xe2x80x2-[1,3]dioxolane] or (g) 8-aza-bicyclo[3.2.1]octanyl optionally substituted with one or more substituents independently selected from the group consisting of oxo and hydroxy. Even more particularly, the present invention provides such compounds, and pharmaceutically acceptable salts thereof, wherein R1 is methyl or chloro, R2 is methyl or chloro, and R5 is hydroxy.
In addition, more particularly, the present invention provides compounds of Formula I, and pharmaceutically acceptable salts thereof, wherein R4 is xe2x80x94C(O)NR19R20, R19 is hydrogen; and R20 is (a) cyclopentyl optionally substituted with one or more xe2x80x94CH2OH, (b) bicyclo[2.2.1]hept-2-yl optionally substituted with one or more substituents independently selected from the group consisting of xe2x80x94CH2OH and methyl, or (c) bicyclo[3.1.1]hept-3-yl optionally substituted with one or more methyl. Even more particularly, the present invention provides such compounds, and pharmaceutically acceptable salts thereof, wherein R1 and R2 are each chloro or dibromo, and R5 is hydroxy.
In addition, more particularly, the present invention provides compounds of Formula I, and pharmaceutically acceptable salts thereof, wherein R4 is xe2x80x94C(O)NR19R20; R19 and R20 are taken together with N to form het; het is (a) piperidinyl optionally substituted with one or more substituents independently selected from the group consisting of methyl and phenyl, (b) pyrrolidinyl, (c) azepanyl, (d) indolinyl or (e) 3,4-dihydro-1H-isoquinolinyl. Even more particularly, the present invention provides such compounds, and pharmaceutically acceptable salts thereof, wherein R1 and R2 are each chloro and R5 is hydroxy.
In addition, more particularly, the present invention provides compounds of Formula I, and pharmaceutically acceptable salts thereof, wherein R4 is xe2x80x94CH2xe2x80x94NR17R18; R17 is hydrogen; and R18 is (a) phenyl optionally substituted with one or more substituents independently selected from methyl and fluoro, (b) benzo[1,3]dioxol-5-yl or (c) indanyl. Even more particularly, the present invention provides such compounds, and pharmaceutically acceptable salts thereof, wherein R1 and R2 are each chloro or bromo and R5 is hydroxy.
In addition, more particularly, the present invention provides compounds of Formula I, and pharmaceutically acceptable salts thereof, wherein R4 is xe2x80x94CH2xe2x80x94NR17R18; R17 and R18 are taken together with the nitrogen atom to which they are attached to form het; and het is piperidinyl optionally substituted with one or more methyl. Even more particularly, the present invention provides such compounds, and pharmaceutically acceptable salts thereof, wherein R1 and R2 are each chloro and R5 is hydroxy.
In addition, more particularly, the present invention provides compounds of Formula I, and pharmaceutically acceptable salts thereof, wherein R4 is xe2x80x94NR19xe2x80x94C(O)xe2x80x94R20; R19 is hydrogen; and R20 is (a) cyclohexyl, (b) phenyl optionally substituted with one or more substituents independently selected from the group consisting of xe2x80x94OCF3, -fluoro and xe2x80x94CF3, (c) -isoxazolyl optionally substituted with methyl or (d) xe2x80x94(C3-C5)alkyl. Even more particularly, the present invention provides such compounds, and pharmaceutically acceptable salts thereof, wherein R1 and R2 are each chloro and R5 is hydroxy.
In addition, more particularly, the present invention provides compounds of Formula I, and pharmaceutically acceptable salts thereof, wherein R4 is xe2x80x94S(O)2R22; and R22 is (a) phenyl optionally substituted with one or more substituents independently selected from the group consisting of methyl and ethyl, (b) indanyl or (c) xe2x80x94(CH2)xe2x80x94(C4-C6) cycloalkyl. Even more particularly, the present invention provides such compounds, and pharmaceutically acceptable salts thereof, wherein R1 and R2 are each chloro and R5 is hydroxy.
In addition, more particularly, the present invention provides compounds of Formula I, and pharmaceutically acceptable salts thereof, wherein R4 is xe2x80x94C(R14)(R15)(R16); R14 is hydroxy; R15 is hydrogen; and R16 is (a) phenyl optionally substituted with one or more fluoro or (b) xe2x80x94(C1-C5)alkyl. Even more particularly, the present invention provides such compounds, and pharmaceutically acceptable salts thereof, wherein R1 is methyl, chloro or bromo; and R2 is methyl, chloro or bromo.
In addition, more particularly, the present invention provides compounds of Formula I, and pharmaceutically acceptable salts thereof, wherein R4 is xe2x80x94C(R14)(R15)(R16); R14 is hydrogen or methyl; R15 is hydrogen; and R16 is (a) phenyl optionally substituted with one or more fluoro or (b) xe2x80x94(C1-C5)alkyl. Even more particularly, the present invention provides such compounds, and pharmaceutically acceptable salts thereof, wherein R1 is methyl, chloro or bromo; R2 is methyl, chloro or bromo; and R5 is hydroxy.
In addition, more particularly, the present invention provides compounds of Formula I, and pharmaceutically acceptable salts thereof, wherein R4 is xe2x80x94C(R14)(R15)(R16); R14 and R15 are taken together with the carbon atom to which they are attached to form a carbonyl group; and R16 is (a) phenyl optionally substituted with one or more fluoro (b) or xe2x80x94(C1-C5)alkyl. Even more particularly, the present invention provides such compounds, and pharmaceutically acceptable salts thereof, wherein R1 is methyl, chloro or bromo; R2 is methyl, chloro or bromo; and R5 is hydroxy.
In addition, more particularly, the present invention provides compounds of Formula I, and pharmaceutically acceptable salts thereof, wherein R4 is xe2x80x94NR21xe2x80x94C(O)xe2x80x94NR21R22; each R21 is hydrogen; and R22 is phenyl optionally substituted with one or more chloro. Even more particularly, the present invention provides such compounds, and pharmaceutically acceptable salts thereof, wherein R1 and R2 are each methyl or chloro; and R5 is hydroxy.
In addition, more particularly, the present invention provides compounds of Formula I, and pharmaceutically acceptable salts thereof, wherein R4 is NR21xe2x80x94S(O)2xe2x80x94R22; R21 is hydrogen; and R22 is xe2x80x94(C0-C2)alkyl-phenyl optionally substituted with one or more fluoro. Even more particularly, the present invention provides such compounds, and pharmaceutically acceptable salts thereof, wherein R1 is chloro, methyl or bromo; R2 is chloro, methyl or bromo; and R5 is hydroxy.
In another aspect, the present invention provides compounds of Formula I, and prodrugs, isomers and pharmaceutically acceptable salts thereof, wherein R1 and R2 are each independently chloro or methyl; R3 is hydrogen; R4 and R5 are taken together to form 
R6 is hydrogen; and R32 is hydrogen or methyl.
In another aspect, the present invention provides compounds of Formula I, and prodrugs, isomers and pharmaceutically acceptable salts thereof, wherein R3 is hydrogen, R4 is Br, R5 is hydroxy or methoxy, R6 is hydrogen and R7 is hydrogen. More particularly, the present invention provides such compounds, and pharmaceutically acceptable salts thereof, wherein R1 and R2 are each methyl. Even more particularly, the present invention provides such compounds, and pharmaceutically acceptable salts thereof, wherein R8 is xe2x80x94C(O)NR10R11; R10 is hydrogen; and R11 is (a) xe2x80x94CH2-furanyl (b) xe2x80x94CH2-phenyl optionally substituted with one or more CF3, (c) xe2x80x94CH2-cyclohexyl optionally substituted with one or more CN, (d) xe2x80x94CH2-pyridinyl, (e) xe2x80x94(CH2)3-imidazolyl or (f) xe2x80x94(CH2)2xe2x80x94N(CH3)2.
In addition, more particularly, the present invention provides compounds of Formula I, and pharmaceutically acceptable salts thereof, wherein R8 is xe2x80x94C(O)NR10R11; R10 and R11 are taken together with the nitrogen atom to which they are attached to form het; and het is (a) thiazolidinyl or (b) 4-oxo-piperidinyl optionally substituted with one or more carboxylic acid methyl ester.
In addition, more particularly, the present invention provides compounds of Formula I, and pharmaceutically acceptable salts thereof, wherein R8 is xe2x80x94C(O)OR9; and R9 is xe2x80x94(CH2)2-piperazinyl optionally substituted with one or more 4-acetyl-phenyl.
Unless otherwise provided herein:
xe2x80x9cAlkylxe2x80x9d means a straight or branched hydrocarbon chain radical, including as the case may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl and the like. For example, alkyl groups include groups such as the following xe2x80x94(C1-C4)alkyl, xe2x80x94(C1-C6)alkyl, xe2x80x94(C1-C12)alkyl and xe2x80x94(C7-C12)alkyl. An alkyl group may be optionally substituted with one or more substituents, preferably one to three substitutents. For example, an alkyl group may be optionally substituted with one or more substituents independently selected from Group V, as defined above, preferably one to three substituents independently selected from Group V.
xe2x80x9cAlkenylxe2x80x9d means a straight or branched unsaturated, univalent aliphatic radical.
xe2x80x9cAlkoxyxe2x80x9d means an alkyl radical which is attached to the remainder of the molecule by oxygen, including as the case may be, for example, methoxy.
xe2x80x9cAlkynylxe2x80x9d means a straight or branched acyclic hydrocarbon radical with one triple bond, including as the case may be, for example, acetylene.
xe2x80x9cCarbocyclicxe2x80x9d (carbocycle) means an unsaturated, or a partially or fully saturated ring having only carbon atoms in its nucleus, including as the case may be an aryl (an organic radical derived from an aromatic hydrocarbon by the removal of one atom, e.g., phenyl from benzene, also including, for example, naphthyl). A carbocyclic ring may be optionally substituted with one or more substituents, preferably one to three substituents. For example, a carbocyclic ring may be optionally substituted with one or more substituents independently selected from Group V, as defined above, preferably one to three substituents independently selected from Group V.
xe2x80x9cCycloalkanexe2x80x9d means a saturated, monocyclic hydrocarbon, including as the case may be, for example, cyclohexane.
xe2x80x9cCycloalkylxe2x80x9d means a monocyclic or polycyclic radical derived from a cycloalkane, including as the case may be, for example, cyclopentyl and cyclohexyl. For example, cycloalkyl groups include groups such as xe2x80x94(C3-C10)cycloalkyl. A cycloalkyl group may be optionally substituted with one or more substituents, preferably one to four substituents. For example, a cycloalkyl group may be optionally substituted with one or more substituents independently selected from Group V, as defined above, preferably one to four substituents independently selected from Group V.
xe2x80x9cArylxe2x80x9d means an organic radical derived from an aromatic hydrocarbon by the removal of one atom, for example, phenyl from benzene. Other aryl groups include, for example, naphthyl and biphenyl. An aryl group may be optionally substituted with one or more substituents, preferably one to three substituents. For example, an aryl group may be optionally substituted with one or more substituents independently selected from Group Z, as defined above, preferably one to three substituents independently selected from Group Z.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d means a radical derived from the elements fluorine, chlorine, bromine or iodine.
xe2x80x9cHeterocyclicxe2x80x9d (xe2x80x9cheterocyclexe2x80x9d or xe2x80x9chetxe2x80x9d), as used herein, unless otherwise indicated, includes aromatic and non-aromatic heterocyclic groups containing one or more heteroatoms, generally 1 to 4 heteroatoms, each selected from O, S and N, wherein each heterocyclic group has from 4-10 atoms in its ring system. Non-aromatic heterocyclic groups include groups having only 4 atoms in their ring system, but aromatic heterocyclic groups must have at least 5 atoms in their ring system. The heterocyclic groups include benzo-fused ring systems and ring systems substituted with one or more oxo moieties. An example of a 4 membered heterocyclic group is azetidinyl (derived from azetidine). An example of a 5 membered heterocyclic group is thiazolyl and an example of a 10 membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydroquinolyl, tetrahydroisoquinolyl, piperidino, piperidyl, morpholino, morpholinyl, thiomorpholino, thiomorpholinyl, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furanyl, benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups may be C-attached or N-attached where such is possible. For instance, a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). A heterocyclic group may be optionally substituted with one or more substituents, preferably one to three substituents. For example, a heterocyclic group may be optionally substituted with one or more substituents independently selected from Group Z, as defined above, preferably one to three substituents independently selected from Group Z.
Where heterocyclic groups are specifically recited or covered as substituents for the compounds of Formula I, it is understood that, unless specifically noted otherwise, all suitable isomers of such heterocyclic groups are intended.
xe2x80x9cHydratexe2x80x9d is a crystalline form of a compound or salt thereof, containing one or more molecules of water of crystallization, i.e., a compound of Formula I or a salt thereof, containing water combined in the molecular form.
xe2x80x9cPharmaceutically acceptablexe2x80x9d means that the carrier, diluent, vehicle excipients and/or salt must be compatible with the other ingredients of the formulation, and not deleterious to the recipient thereof.
xe2x80x9cPharmaceutically acceptable saltsxe2x80x9d of the compounds of this invention may be formed of the compound itself, prodrugs, e.g. esters, isomers and the like, and include all of the pharmaceutically acceptable salts which are most often used in pharmaceutical chemistry; for example, salts may be formed with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, carboxylic acids, sulfonic acids including such agents as naphthalenesulfonic, ethanesulfonic, hydroxyethanesulfonic, methanesulfonic (xe2x80x9cmesylatexe2x80x9d), benzenesulfonic (xe2x80x9cbesylatexe2x80x9d) and toluenesulfonic acids, e.g., p-toluenesulfonic (xe2x80x9ctosylatexe2x80x9d), sulfuric acid, nitric acid, phosphoric acid, tartaric acid, pyrosulfuric acid, metaphosphoric acid, succinic acid, formic acid, phthalic acid, malic acid, maleic acid, lactic acid, ascorbic acid, glycollic acid, gluconic acid, mandelic acid, glutamic acid, aspartic acid, fumaric acid, pyruvic acid, phenylacetic acid, pamoic acid, nicotinic acid, and the like. Suitable pharmaceutically acceptable salts also include alkali metal salts (e.g. sodium, potassium salts), alkaline earth metal salts (e.g. magnesium, calcium salts), amine salts (e.g. ammonium, alkylammonium, dialkylammonium, trialkylammonium, tetraalkylammonium, diethanolammonium, tri-ethanolammonium and guanidinium salts). Preferred salts include salts of organic acids selected from formic, acetic, trifluoroacetic, propionic, benzoic, citric, maleic, tartaric, methanesulfonic, benzenesulfonic or toluenesulfonic; salts of inorganic acids selected from hydrochloric, hydrobromic, sulfuric or phosphoric; salts of amino acids selected from aspartic and glutamic; and salts of sodium and potassium.
xe2x80x9cPolymorphxe2x80x9d is a compound or salt thereof, such as the compound of Formula I or a salt thereof, which occurs in two or more forms.
xe2x80x9cProdrugxe2x80x9d is a drug precursor which, following administration, releases the drug in vivo via some chemical or physiological process (e.g., a prodrug on being brought to the physiological pH or through enzyme action is converted to the desired drug form); exemplary prodrugs upon cleavage release the corresponding free acid, and such hydrolyzable ester-forming residues of the compounds of Formula I include but are not limited to those having a carboxyl moiety wherein the free hydrogen is replaced by (C1-C4)alkyl, (C2-C7)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxy-carbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxy-carbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(C1-C2)alkylamino(C2-C3)alkyl (such as b-dimethylaminoethyl), carbamoyl-(C1-C2)alkyl, N,N-di(C1-C2)alkylcarbamoyl-(C1-C2)alkyl and piperidino-, pyrrolidino- or morpholino(C2-C3)alkyl.
xe2x80x9cRadicalxe2x80x9d is a group of atoms that behaves as a single atom in a chemical reaction, e.g., an organic radical is a group of atoms which confers characteristic properties on a compound containing it, or which remains unchanged during a series of reactions.
xe2x80x9cSolvatexe2x80x9d is a molecular or ionic complex of molecules or ions of a solvent with those of a solute; a xe2x80x9csolvatexe2x80x9d wherein the solvent is water, forms xe2x80x9chydratesxe2x80x9d or hydrated ions.
xe2x80x9cSpirocycloalkylxe2x80x9d means cycloalkyl having a spiro union (the union formed by a single atom which is the only common member of the rings).
xe2x80x9cTreating,xe2x80x9d xe2x80x9ctreatxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d includes, inter alia, preventative (e.g., prophylactic), palliative and curative treatment.
xe2x80x9cTherapeutically effective amountxe2x80x9d means an amount of a compound that ameliorates, attenuates, or eliminates one or more symptoms of a particular disease or condition or prevents or delays the onset of one of more symptoms of a particular disease or condition.
xe2x80x9cPatientxe2x80x9d means animals, such as dogs, cats, cows, horses, sheep, and humans. Particularly preferred patients are mammals, including both males and females.
The present invention provides methods of treating a condition selected from obesity, overweight condition, hyperlipidemia, thyroid disease, hypothyroidism, thyroid cancer, diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, hypercholesteremia, depression, osteoporosis, cardiac arrhythmias, glaucoma and congestive heart failure in a mammal (including a human being) which comprise administering to said mammal a therapeutically effective amount of a compound of Formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug, as described above. Especially preferred are such methods wherein said condition is obesity. Such methods further comprise administering an anorectic agent or a lipase inhibitor.
In another aspect, the present invention provides methods of treating a condition selected from obesity, overweight condition, hyperlipidemia, thyroid disease, hypothyroidism, thyroid cancer, diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, hypercholesteremia, depression, osteoporosis, cardiac arrhythmias, glaucoma and congestive heart failure in a mammal (including a human being) which comprise administering to said mammal a therapeutically effective amount of a compound of Formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug, as described above, and an anorectic agent.
In another aspect, the present invention provides methods of treating a condition selected from obesity, overweight condition, hyperlipidemia, thyroid disease, hypothyroidism, thyroid cancer, diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, hypercholesteremia, depression, osteoporosis, cardiac arrhythmias, glaucoma and congestive heart failure in a mammal (including a human being) which comprise administering to said mammal a therapeutically effective amount of a compound of Formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug, as described above, and a lipase inhibitor.
In a preferred aspect, the present invention provides methods of treating obesity in mammals (including a human being) which comprise administering to said mammal an obesity treating effective amounts of a compound of Formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug, as described above. In yet another preferred aspect, the present invention provides methods of inducing weight loss in a mammal which comprise administering to said mammal a therapeutically effective amount of a compound of Formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug.
In another aspect, the present invention provides methods of treating obesity in mammals (including a human being) which comprise administering to said mammal obesity treating effective amounts of a compound of Formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug, as described above, and an anorectic agent.
In another aspect, the present invention provides methods of treating obesity, in a mammal (including a human being) which comprise administering to said mammal obesity treating effective amounts of a compound of Formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug, as described above, and a lipase inhibitor.
In another aspect, the present invention provides pharmaceutical compositions comprising an amount of a compound of Formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug, as described above, and a pharmaceutically acceptable vehicle, diluent or carrier.
In another aspect, the present invention provides pharmaceutical compositions comprising a compound of Formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug, as described above; an anorectic agent and a pharmaceutically acceptable vehicle, diluent or carrier.
In another aspect, the present invention provides pharmaceutical compositions comprising a compound of Formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug, as described above; a lipase inhibitor and a pharmaceutically acceptable vehicle, diluent or carrier.
In another aspect, the present invention provides pharmaceutical compositions for treating a condition selected from obesity, overweight condition, hyperlipidemia, thyroid disease, hypothyroidism, thyroid cancer, diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, hypercholesteremia, depression, osteoporosis, cardiac arrhythmias, glaucoma and congestive heart failure in a mammal (including a human being) comprising an amount of a compound of Formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug, as described above, and a pharmaceutically acceptable vehicle, diluent or carrier.
In another aspect, the present invention provides pharmaceutical compositions for treating a condition selected from obesity, overweight condition, hyperlipidemia, thyroid disease, hypothyroidism, thyroid cancer, diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, hypercholesteremia, depression, osteoporosis, cardiac arrhythmias, glaucoma and congestive heart failure in a mammal (including a human being) comprising a compound of Formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug, as described above; an anorectic agent, and a pharmaceutically acceptable vehicle, diluent or carrier.
In another aspect, the present invention provides pharmaceutical compositions for treating a condition selected from obesity, overweight condition, hyperlipidemia, thyroid disease, hypothyroidism, thyroid cancer, diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, hypercholesteremia, depression, osteoporosis, cardiac arrhythmias, glaucoma and congestive heart failure in a mammal (including a human being) comprising a compound of Formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug, as described above; a lipase inhibitor, and a pharmaceutically acceptable vehicle, diluent or carrier.
In another preferred aspect, the present invention provides pharmaceutical compositions for treating obesity in a mammal (including a human being) comprising a compound of Formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug, as described above, and a pharmaceutically acceptable vehicle, diluent or carrier. In yet another preferred aspect, the present invention provides pharmaceutical compositions for inducing weight loss comprising a weight loss-treating amount of a compound of Formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug; and a pharmaceutically acceptable carrier, vehicle or diluent.
In a preferred aspect, the present invention provides pharmaceutical compositions for treating obesity in a mammal (including a human being) comprising a compound of Formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug, as described above; an anorectic agent, and a pharmaceutically acceptable vehicle, diluent or carrier.
In yet another aspect, the present invention provides pharmaceutical compositions for treating obesity in a mammal (including a human being) comprising a compound of Formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug, as described above; a lipase inhibitor, and a pharmaceutically acceptable vehicle, diluent or carrier.
In another aspect, the present invention provides kits for the treatment of a condition selected from obesity, overweight condition, hyperlipidemia, thyroid disease, hypothyroidism, thyroid cancer, diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, hypercholesteremia, depression, osteoporosis, cardiac arrhythmias, glaucoma and congestive heart failure which comprise: a first compound, said first compound being a compound of Formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug, as described above, and a pharmaceutically acceptable vehicle, carrier or diluent, in a first unit dosage form; a second compound, said second compound being an anorectic agent or a lipase inhibitor, and a pharmaceutically acceptable vehicle, carrier or diluent, in a second unit dosage form; and a container for containing said first and second dosage forms; wherein the amounts of said first and second compounds result in a therapeutic effect.
In another preferred aspect, the present invention provides kits for the treatment of a obesity which comprise: a first compound, said first compound being a compound of Formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug, as described above, and a pharmaceutically acceptable vehicle, carrier or diluent, in a first unit dosage form; a second compound, said second compound being an anorectic agent or a lipase inhibitor, and a pharmaceutically acceptable vehicle, carrier or diluent, in a second unit dosage form; and a container.
In another aspect, the present invention provides kits for the treatment of a condition selected from the group consisting of obesity, overweight condition, hyperlipidemia, thyroid disease, hypothyroidism, thyroid cancer, diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, hypercholesteremia, depression, osteoporosis, cardiac arrhythmias, glaucoma and congestive heart failure which comprises:
a first compound, said first compound being a compound of Formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug and a pharmaceutically acceptable carrier, vehicle or diluent, in a first unit dosage form;
a second compound, said second compound being useful for the treatment of a condition selected from the group consisting of obesity, overweight condition, hyperlipidemia, thyroid disease, hypothyroidism, thyroid cancer, diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, hypercholesteremia, depression, osteoporosis, cardiac arrhythmias, glaucoma and congestive heart failure, and a pharmaceutically acceptable carrier, vehicle or diluent in a second unit dosage form; and
a container for containing said first and second dosage forms; wherein the amounts of said first and second compounds result in a therapeutic effect.
In another aspect, the present invention provides methods of treating a condition selected from the group consisting of obesity, overweight condition, hyperlipidemia, thyroid disease, hypothyroidism, thyroid cancer, diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, hypercholesteremia, depression, osteoporosis, cardiac arrhythmias, glaucoma and congestive heart failure in a mammal which comprises administering to said mammal a therapeutically effective amount of a compound of Formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug, in combination with at least one additional compound useful for treating a condition selected from the group consisting of obesity, overweight condition, hyperlipidemia, thyroid disease, hypothyroidism, thyroid cancer, diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, hypercholesteremia, depression, osteoporosis, cardiac arrhythmias, glaucoma and congestive heart failure.
In another aspect, the present invention provides pharmaceutical compositions comprising an amount of a compound of Formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug; at least one additional compound useful for treating a condition selected from the group consisting of obesity, overweight condition, hyperlipidemia, thyroid disease, hypothyroidism, thyroid cancer, diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, hypercholesteremia, depression, osteoporosis, cardiac arrhythmias, glaucoma and congestive heart failure in a mammal; and a pharmaceutically acceptable carrier, vehicle or diluent.